Vaccines protect against a wide variety of infectious diseases. Many modern vaccines are therefore made from protective antigens of the pathogen, which are isolated by molecular cloning and purified. These vaccines are known as ‘subunit vaccines’. The development of subunit vaccines has been the focus of considerable research in recent years. The emergence of new pathogens and the growth of antibiotic resistance have created a need to develop new vaccines and to identify further candidate molecules useful in the development of subunit vaccines. Likewise the discovery of novel vaccine antigens from genomic and proteomic studies is enabling the development of new subunit vaccine candidates, particularly against bacterial pathogens. However, although subunit vaccines tend to avoid the side effects of killed or attenuated pathogen vaccines, their ‘pure’ status means that subunit vaccines do not always have adequate immunogenicity to confer protection.
An approach to improve the efficacy of vaccine compositions is to provide multivalent vaccines comprising dominant antigens that provoke both a B cell and T cell response thereby mounting a more rigorous immune response in the subject receiving the vaccine. A typical multivalent vaccine might be a whole cell vaccine comprising multiple antigenic molecules. For example the Bacillus Calmette Guerin [“BCG”] vaccine includes an attenuated Mycobacterium bovis strain that provokes protective immunity in humans. For many pathogens chemical or heat inactivation while it may give rise to vaccine immunogens that confer protective immunity also gives rise to side effects such as fever and injection site reactions. In the case of bacteria, inactivated organisms tend to be so toxic that side effects have limited the application of such crude vaccine immunogens and therefore vaccine development has lagged behind drug-development. Moreover, effective vaccine development using whole cell inactivated organisms suffers from problems of epitope masking, immunodominance, low antigen concentration and antigen redundancy.
There is therefore a continuing need to identify antigens that are protective and can be used in multivalent vaccines of bacterial pathogens. The combinations may be used in combination with non-protein immunogenic molecules such as polysaccharide antigens and anti-bacterial agents to provide a treatment regimen for control of bacterial infection. It is also within the scope of this disclosure to modify the treatment regimen to immunize subjects with a series of temporally separated administrations as an alternative to the administration of a single vaccine comprising multiple antigens.
This disclosure therefore relates to immunogenic compositions and vaccines, typically multivalent vaccines but also monovalent vaccines and their use in the prophylaxis and treatment of bacterial infections. We disclose polypeptides that are typically membrane spanning proteins that include an extracellular domain. For example DivlB is an integral membrane protein comprising an intracellular domain, an intermembrane domain and an extracellular domain. The related gene DivlC is also an integral membrane protein the extracellular domain. This disclosure also relates to antigens encoded by the genes PheP, YdiE and FtsL each of which has an extramembranous domain. Typically, it would be desirable to develop vaccines against Gram positive bacterial pathogens which include, by example: Bacillus anthracis, Clostridium botulinum, Clostridium difficile, Enterococcus faecalis, Mycobacterium tuberculosis, Staphylococcus spp, Streptococcus group A, Streptococcus group B, Streptococcus pneumonia. Moreover the development of vaccines against Gram negative bacterial pathogens such as, Helicobacter pylori, Neisseria gonorrhoea, Neisseria meningitidis type B, Shigella flexneri, Escherichia coli, Haemophilus influenzae, Chlamydia trachomatis, Pseudomonas aeruginosa, Yersinia pestis, Burkholderia mallei or B. pseudomallei would also be desirable.